Sinha Mousumi, Jagadeesan Rahul, Kumar Neeraj, Saha Satabdi, Kothandan Gugan, Kumar Diwakar
Department of Microbiology, Assam University, Silchar, Assam, India.
CAS in Crystallography and Biophysics, Guindy Campus, University of Madras, Chennai, Tamil Nadu, India.
J Biomol Struct Dyn. 2022 May;40(8):3371-3384. doi: 10.1080/07391102.2020.1847194. Epub 2020 Nov 17.
Myo-inositol is one of the vital nutritional requirements for the parasites' survival and virulence in the mammalian host. . Myo-inositol-1-phosphate synthase (MIPS) is responsible for the synthesis of myo-inositol in , which plays a vital role in virulence to mammalian hosts. Earlier studies suggest MIP synthase as a potential drug target against which valproate was used as a drug. So, MIP synthase can be used as a target for anti-leishmanial drugs, and its inhibition may help in preventing leishmaniasis. The present study aims to identify valproate's potent analogs as drugs against MIP synthase of (MIPS) with minimum side effects and toxicity to host.In this study, the three-dimensional structure of MIPS was built, followed by active site prediction. Ligand-based virtual screening was done using hybrid similarity recognition methods. The best 123 valproate analogs were filtered based on their quantitative structure activity relationship (QSAR) properties and were docked against -MIPS using FlexX, PyRx and iGEMDOCK software. The topmost five ligands were selected for molecular dynamics simulation and pharmacokinetic analysis based on the docking score. Simulation studies up to 30 ns revealed that all five lead molecules bound with -MIPS throughout MD simulation and there was no variation in their backbone. All the chosen inhibitors exhibited good pharmacokinetics/ADMET predictions with an excellent absorption profile, metabolism, oral bioavailability, solubility, excretion, and minimal toxicity, suggesting that these inhibitors may further be developed as anti-leishmaniasis drugs to prevent the spread of leishmaniasis.Communicated by Ramaswamy H. Sarma.
肌醇是寄生虫在哺乳动物宿主中生存和致病的重要营养需求之一。肌醇-1-磷酸合酶（MIPS）负责肌醇的合成，其在对哺乳动物宿主的致病性中起着至关重要的作用。早期研究表明MIP合酶是一个潜在的药物靶点，丙戊酸盐曾被用作针对该靶点的药物。因此，MIP合酶可作为抗利什曼原虫药物的靶点，对其抑制可能有助于预防利什曼病。本研究旨在确定丙戊酸盐的有效类似物作为针对利什曼原虫（Leishmania）MIP合酶的药物，使其对宿主的副作用和毒性最小。在本研究中，构建了MIPS的三维结构，随后进行活性位点预测。使用混合相似性识别方法进行基于配体的虚拟筛选。根据定量构效关系（QSAR）特性筛选出最佳的123种丙戊酸盐类似物，并使用FlexX、PyRx和iGEMDOCK软件将其与利什曼原虫MIPS进行对接。根据对接分数选择排名最靠前的五种配体进行分子动力学模拟和药代动力学分析。长达30纳秒的模拟研究表明，在整个分子动力学模拟过程中，所有五种先导分子均与利什曼原虫MIPS结合，其主链没有变化。所有选定的抑制剂均表现出良好的药代动力学/药物代谢动力学预测结果，具有出色的吸收特性、代谢、口服生物利用度、溶解度、排泄以及最小的毒性，这表明这些抑制剂可能进一步被开发为抗利什曼病药物以预防利什曼病的传播。由拉马斯瓦米·H·萨尔马通讯。
